The serotonin transporter (SERT) is an integral membrane protein found on pre-synaptic terminals of serotonin (5-HT) neurons in the central nervous system. The SERT is responsible for clearance of 5-HT from the synaptic cleft after neuronal firing. Abnormalities in SERT function and/or changes in SERT receptor densities within the brain have been implicated in a variety of neurological and mental health disorders. In an effort to quantify SERT changes through the use of functional imaging studies of living brain, a comprehensive effort has involved the generation of the requisite radiotracers. A strong need for the discovery of new SERT radioligands remains. It is the objective of this renewal proposal to ascertain the identity of those quipazine-based ligands which may serve as positron emission tomography (PET) dynamic brain imaging agents for the serotonin transporter. This effort will use a discovery paradigm constructed with a sequence of specific aims, which include: l) the chemical synthesis of non-radioactive substituted quipazine ligands; 2) the in vitro pharmacological assessments of the ligands using rat tissues; 3) the formation of radiolabeled forms of the ligands (tritium and also carbon-11 and fluorine-18 variants); 4) evaluation of the radiotracers both in vivo and ex vivo with rat models to study tracer distributions and binding profiles; and 5) surveys of metabolic dispositions. By these investigations we will be able to judge as to whether select quipazine-based ligands, which contain beta emitting labels, possess value as prospective dynamic brain imaging agents.